Risk Categories for Pediatric Patients With Medulloblastoma

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In an analysis from the international phase III SJMB03 trial reported in the Journal of Clinical Oncology, Gajjar et al identified lower- and higher-risk groups of pediatric patients with medulloblastoma based on molecular and clinical risk factors.

Study Details

SJMB03 is a phase III trial of risk-adapted therapy, with the objective of identifying the frequency and clinical significance of biologic variants and genetic alterations in pediatric patients with medulloblastoma. A total of 330 patients enrolled in the trial between September 2003 and June 2013; they were stratified into average-risk (n = 277) or high-risk (n = 103) groups based on metastatic status and extent of resection.

Medulloblastomas were molecularly classified into subgroups (wingless [WNT], sonic hedgehog [SHH], group 3, and group 4) and subtypes based on DNA methylation profiles and overlaid with gene mutations from next-generation sequencing (NGS). 

The co-primary endpoints were to assess the relationship between ERBB2 protein expression and progression-free survival, as well as to estimate the frequency of mutations associated with WNT and SHH tumors. Clinical and molecular risk factors were modeled to construct new risk classification categories.

Key Findings

In the entire cohort, 5-year progression-free survival was 83.2% for average-risk patients and 58.7% for high-risk patients.  

Among 120 patients with available ERBB2 protein expression status (84 average-risk and 36 high-risk patients), there was no significant difference in 5-year progression-free survival between 75 ERBB2-positive vs 45 ERBB2-negative patients overall (71.8% vs 70.6%, P = .74) or when analyzed by high- and low-risk groups (P = .71).

Among 305 patients assessed by methylation array, molecular classification of tumors was WNT for 53, SHH for 48, group 3 for 65, and group 4 for 139. Among 293 assessed by NGS, classification was WNT for 49, SHH for 48, group 3 for 62, and group 4 for 134.

In the NGS cohort, mutations in CTNNB1 (96%), DDX3X (37%), and SMARCA4 (24%) were the most common in WNT tumors; mutations in PTCH1 (38%), TP53 (21%), and DDX3X (19%) were the most common in SHH tumors.

Based on methylation analysis, combined group 3 and group 4 patients were further classified into eight subtypes: subtype I (n = 13), subtype II (n = 28), subtype III (n = 18), subtype IV (n = 8), subtype V (n =19), subtype VI (n = 17), subtype VII (n = 50), and subtype VIII (n = 51). Three new risk groups were identified among combined group 3 and 4 patients:

  • Low = patients with M0 disease and subtype VII
  • Intermediate = patients with M0 and subtype I, II, IV, V, VI, and VIII
  • High = patients with M1 disease or subtype III or MYC-amplified.

Clinical and molecular risk factor analysis then identified patient groups with low risk and high risk. Three low-risk groups consisting of patients with WNT, low-risk SHH, and low-risk group 3 and 4 tumors had 5-year progression-free survival of more than 90%. Two very high-risk groups consisting of patients with high-risk SHH and high-risk group 3 and 4 tumors had 5-year progression-free survival of lower than 60%.

The investigators concluded, “These results establish a new risk stratification for future medulloblastoma trials.”

Giles W. Robinson, MD, of the Division of Neuro-Oncology, St. Jude Children’s Research Hospital, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the American Lebanese Syrian Associated Charities, St. Jude Children’s Research Hospital, National Cancer Institute, Sontag Foundation, and others. For full disclosures of the study authors, visit

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